Autophagy · What Is It, Health Benefits, Role in Cancer, and More

Autophagy, meaning “self-eating,” is an intracellular degradation process that allows cells to recycle damaged intracellular components to generate energy and provide building blocks to create new cellular structures.  

In physiological conditions, autophagy acts as a housekeeping mechanism to ensure that damaged organelles and proteins are rapidly digested and cleared from the cell, so they don’t build up and prevent cells from functioning correctly. In response to metabolic stressors (e.g., nutrient deprivation, oxidative stress, or DNA damage), autophagic activity is upregulated to keep up with the increased metabolic demands, allow cells to work efficiently, and survive under stress conditions. For example, autophagy is essential in times of nutrient deprivation as it enables cells to reutilize their cell components for energy and replace the depleted intracellular parts. In addition, autophagic activity contributes to the mobilization of cellular energy stores, like glucose, amino acids, and nucleic acids, which can then become available for energy production.  

In recent years, defects in autophagy-related genes have been associated with the development of several disorders, including cancer and neurodegenerative diseases like Alzheimer disease. Like many other physiologic processes, autophagy declines with age, likely contributing to accumulation of damaged cells and proteins. Various animal models and cellular studies indicate that increased autophagy activity may play a role in improved longevity and a longer lifespan. However, research on the topic is still ongoing, and further investigation is needed.  

The process of autophagy starts when autophagy-related proteins are recruited sequentially to form a cup-shaped membrane called a phagophore. The phagophore then extends and surrounds damaged intracellular components by creating a double-membrane vesicle around them called an autophagosome. Once formed, the autophagosome undergoes a maturation process as it travels through the cell’s cytoplasm before fusing with an organelle called a lysosome. When the lysosome and the autophagosome fuse together, their contents merge, forming a structure known as the autophagolysosome. Inside this structure, lysosomal enzymes start destroying the autophagosome contents (i.e., damaged intracellular components). The degradation products, which may include sugars, amino acids, nucleotides, and fatty acids, are then released back into the cytoplasm for future cell use. 

Although the formation of the autophagosome is the most critical and researched mechanism of autophagy, there are two other types of autophagy called microautophagy and chaperone-mediated autophagy. In microautophagy, the lysosome directly engulfs portions of the cytoplasm. In contrast, in chaperone-mediated autophagy, specific chaperone proteins bind to the intracellular cargo and transport it to the lysosome for degradation. 

Autophagy is a cell-survival mechanism that is naturally induced in response to several metabolic stressors, such as nutrient deprivation, organelle or DNA damage, hypoxia, and infection.  

Current research shows that starvation is a primary stimulus that can trigger autophagy. This is partly why fasting diets and calorie restriction have become popular ways to improve health and longevity in recent years. Fasting practices may positively affect certain conditions, including better seizure control for children with epilepsy, possibly due to neuroprotection. Common fasting practices include intermittent fasting, where individuals limit their calorie intake during certain hours of the day or certain days of the week, and prolonged fasting, where individuals may fast for several days at a time. During fasting, individuals may consume water, black coffee, tea, and other calorie-free beverages, but no solid foods or calorie-containing drinks are allowed.  

Although fasting can indeed have health benefits for some individuals, it does come with risks. For example, individuals who undergo fasting diets may experience low energy levels, leading to extreme tiredness, difficulty concentrating, and a low or depressed mood. In addition, skipping meals and severely limiting calories can be dangerous for certain people, including elderly individuals, children, and adolescents; people with a history of eating disorders; high-performance athletes; and individuals who are pregnant or breastfeeding. Additionally, fasting may not be safe for people with diabetes mellitus and individuals who take medications for high blood pressure or heart disease, who are more likely to develop electrolyte imbalances from fasting.